The evolution of systolic blood pressure as a strong predictor of cardiovascular risk and the effectiveness of fixed-dose ARB/CCB combinations in lowering levels of this preferential target

Abstract

Elevated blood pressure is an important cardiovascular risk factor. Although targets for both diastolic blood pressure (DBP) and systolic blood pressure (SBP) are defined by current guidelines, DBP has historically taken precedence in hypertension management. However, there is strong evidence that SBP is superior to DBP as a predictor of cardiovascular events. Moreover, achieving control of SBP is assuming greater importance amongst an aging population. In spite of the growing recognition of the importance of SBP in reducing cardiovascular risk and the emphasis by current guidelines on SBP control, a substantial proportion of patients still fail to achieve SBP targets, and SBP control is achieved much less frequently than DBP control. Thus, new approaches to the management of hypertension are required in order to control SBP and minimize cardiovascular risk. Fixed-dose combination (FDC) therapy is an approach that offers the advantages of multiple drug administration and a reduction in regimen complexity that favors compliance. We have reviewed the latest evidence demonstrating the efficacy in targeting SBP of the most recent FDC products; combinations of the calcium channel blocker (CCB), amlodipine, with angiotensin receptor blockers (ARBs), valsartan or olmesartan. In addition, results from studies with new classes of agent are outlined.

Keywords: angiotensin receptor blocker; calcium channel blocker; combination therapy; hypertension; systolic blood pressure.

Figure 1

Relationship between odds ratios for cardiovascular events and corresponding differences in systolic blood pressure. Reprinted with permission from Staessen JA, Wang JG, Thijs L. 2003. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens, 21:1055–76. Copyright © 2003 Lippincott Williams & Wilkins. The left-hand panel shows the relationship between odds ratios for cardiovascular events (experimental treatment versus reference treatment) and differences between treatments in achieved systolic blood pressure using data from clinical trials of antihypertensive drugs. The meta-regression line, which is shown with its 95% confidence interval, was weighted for the inverse of the variance of the individual odds ratios. The right-hand panel shows the results of more recent trials superimposed on the meta-regression line. Abbreviations: AASK, the African American Study of Kidney disease and hypertension; ABCD/NT, Appropriate Blood Pressure Control in Diabetes trial – tight versus usual blood pressure control in normotensive patients; ALLHAT, Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial; ALLHAT/Aml, Antihypertensive and Lipid- Lowering treatment to prevent Heart Attack Trial – amlodipine versus chlorthalidone; ALLHAT/Lis, Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial – lisinopril versus chlorthalidone; ANBP2, Australian comparative outcome trial of angiotensin-converting enzyme inhibitor- and diuretic-based treatment of hypertension in the elderly; ATMH, Australian Trial in Mild Hypertension; CAPPP, CAptopril Prevention Project; CONVINCE, Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints Trial; DIABHYCAR, the non-insulin-dependent DIAbetes, HYpertension, microalbuminuria or proteinuria, Cardiovascular events, and ramipril study; ELSA, European Lacidipine Study on Atherosclerosis; EWPHE, trial conducted by the European Working Party on High blood pressure in the Elderly; HEP, trial of Hypertension in Elderly Patients in primary care; HOPE, Heart Outcomes Prevention Evaluation study; HOT/LH, Hypertension Optimal Treatment trial – 80 versus 90 mmHg as target diastolic pressure; HOT/MH, Hypertension Optimal Treatment trial – 85 versus 90 mmHg as target diastolic pressure; IDNT2, Irbesartan Diabetic Nephropathy Trial in patients with type-2 diabetes mellitus; INSIGHT, International Nife-dipine GITS Study – Intervention as a Goal for Hypertension Treatment; LIFE/All, Losartan Intervention For Endpoint reduction in hypertension study – all patients; LIFE/DM, Losartan Intervention For Endpoint reduction in hypertension study – diabetic subgroup; MIDAS/NICS/VHAS, combined results of MIDAS, NICS and VHAS; MRC1, Medical Research Council trial of treatment of mild hypertension; MRC2, Medical Research Council trial of treatment of hypertension in older adults; NICOLE, NIsoldipine in Coronary artery disease in LEuven; NORDIL, NOrdic DILtiazem study; PART2, Prevention of Atherosclerosis with Ramipril Trial; PART2/SCAT, combined results of PART2 and SCAT; PATS, Post-stroke Antihypertensive Treatment Study; PREVENT, Prospective Randomized Evaluation of the Vascular Effects Norvasc Trial; PROGRESS/Com, perindopril PROtection aGainst REcurrent Stroke Study – group on combined therapy; PROGRESS/Per, perindopril PROtection aGainst REcurrent Stroke Study – group on single-drug treatment; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; RCT70–80, combined results of four smaller trials published from 1970 through 1980, including HSCS, OSLO, USPHS, and VACS; SCOPE, Study on COgnition and Prognosis in the Elderly; SHEP, Systolic Hypertension in the Elderly Program; STONE, Shanghai Trial of Nifedipine in the Elderly; STOP1, Swedish Trial in Old Patients with hypertension; STOP2/ACEIs, angiotensin-converting enzyme inhibitor arm of STOP2; STOP2/CCBs, calcium-channel blocker arm of STOP2; Syst-China, Systolic hypertension in China trial; Syst-Eur, Systolic hypertension in Europe trial; UKPDS, UKPDS hypertension in diabetes study; UKPDS/CA, UKPDS hypertension in Diabetes Study – captopril versus atenolol; UKPDS/LH, UKPDS hypertension in diabetes study – low versus high on-treatment blood pressure.

Figure 2

Risk ratios for mortality as a result of cardiovascular disease and coronary heart disease in patients treated for hypertension compared with gender- and age-matched hypertensive and normotensive subjects (Derived from Benetos et al 2003). Benetos et al (2003) used data from 8893 treated hypertensive patients and 25,880 untreated age- and gender-matched normotensive and hypertensive control patients to determine the influence of hypertension on cardiovascular mortality. Cardiovascular and coronary mortality were two-fold higher in the treated population. After adjustment for systolic blood pressure (SBP) using Cox regression analysis, the differences between the treated and untreated populations decreased from 96% to 14% (cardiovascular mortality, P = 0.05) and from 99% to 16% (coronary heart disease mortality, p = 0.08). Subsequent adjustment for diastolic blood pressure (DBP) had no further effect on the risk ratios.

Figure 3

Achievement of blood pressure goals in controlled trials of antihypertensive agents. Reproduced with permission from Mancia G, Grassi G. 2002. Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens, 20:1461–4. Copyright © 2002 Lippincott Williams & Wilkins. Mancia and Grassi (2002) summarized the effects of antihypertensive treatment on systolic and diastolic blood pressure (SBP and DBP, respectively) in clinical trials involving patients with essential hypertension. The data show that higher initial blood pressures (B) are associated with larger reductions during treatment (T). Target blood pressure values (SBP, 140 mmHg; DBP, 85–90 mmHg), shown as dotted lines on the graphs, were achieved more frequently for DBP than for SBP. See Figure 1 legend for key to trial names.

Figure 4

Percentage of patients who achieved SBP <140 mmHg and retained DBP ≥ 90 mmHg compared with percentage of patients who achieved DBP < 90 mmHg and retained SBP ≥ 140 mmHg. Reproduced with permission from Waeber B, Mourad JJ. 2006. Targeting systolic blood pressure: the key to controlling combined systolic/diastolic hypertension. Am J Hypertens, 19:985–6. Copyright © 2006 Nature Publishing Group. Data from the STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) study show that patients who achieve a target systolic blood pressure (SBP) < 140 mmHg are also likely to achieve a diastolic blood pressure < 90 mmHg. In contrast, a substantial proportion of patients who achieve DBP < 90 mmHg fail to achieve adequate control of SBP. As demonstrated by the figure, this finding is consistent across a range of treatment regimens.

Figure 5

Systolic blood pressure reductions achieved with a combination of amlodipine and olmesartan (Chrysant et al 2008). In the COACH study (Combination of Olmesartan medoxomil and Amlodipine besylate in Controlling High blood pressure), patients with a seated diastolic blood pressure of 95–120 mmHg at baseline were randomized to receive daily treatment with placebo, olmesartan/amlodipine 20/5 mg, 40/5 mg, or 40/10 mg. The figure shows the mean reduction from baseline in seated systolic blood pressure (SBP) after 8 weeks of treatment.